PROJECT SUMMARY/ABSTRACT Dr. Leah Katzelnick, PhD, MPH is an epidemiologist at the University of California, Berkeley whose work focuses on the viral and immunological determinants of dengue disease in human populations. Her long-term career goal is to identify immune correlates of flaviviral diseases and translate these insights into public health interventions to reduce the burden of disease. Most urgently, she is focused on how to ensure the safety and efficacy of dengue vaccines. Over 3 billion people are at risk of infection with dengue viruses 1-4 (DENV1-4), which are mosquito-borne flaviviruses that cause ~390 million infections, ~100 million cases, and ~500,000 hospitalizations each year. An ideal dengue vaccine would induce protective immunity regardless of the number of prior DENV infections, but currently, the only licensed dengue vaccine significantly increases the risk of severe disease in those without previous DENV infections. Comprehensive evaluation of the benefits and risks of dengue vaccines requires the ability to measure and distinguish the populations of vaccine- induced antibodies that are protective from those capable of causing disease enhancement. In this K01 award, Dr. Katzelnick will develop a unifying framework for testing the theory of antibody-mediated immunity against dengue, determining whether three antibody populations, including possible 'super antibodies' that bind across viral surface proteins, are mechanistic correlates of protection against dengue in the most important human dengue vaccine studies conducted to date. Aim 1 will use formal immune correlates-of-risk analyses to test whether super antibodies, measured via revolutionary antibody-depletion assays, protect against dengue in a case-control study of vaccinated children in the randomized controlled phase 3 trials of the licensed dengue vaccine. Aim 2 evaluates whether super antibodies protect against immunological boost upon challenge as well as whether challenge results in the induction of super antibodies, providing insight into the determinants of protective immunity following natural secondary DENV infections. Aim 3 directly tests neutralizing antibodies as well as super antibodies as correlates of risk and protection against dengue and severe dengue in the longitudinal vaccinated cohort in the Philippines. This aim is the first time these distinct populations of antibodies will be formally evaluated for their ability to protect and enhance disease in humans, using cutting- edge statistical techniques. The mentoring team, which consists of leading experts on the biological and statistical approaches to measuring dengue immune correlates, will advise Dr. Katzelnick on both her proposed research and career development. Her expertise in seroepidemiology will be augmented by formal and informal training in advanced biostatistical methods for evaluating vaccine trials and immune correlates, as well as interdisciplinary professional connections, at UC Berkeley and elsewhere. In sum, the research and career development activities proposed in this award will enable Dr. Katzelnick to establish herself as a leading expert on both natural and vaccine-induced dengue immunity and launch her career independent researcher. !